Pediatrics and Neonatology (2012) 53, 158e163

Available online at www.sciencedirect.com

journal homepage: http://www.pediatr-neonatol.com

REVIEW ARTICLE

Necrotizing Enterocolitis: Old Problem with

New Hope
Shu-Fen Wu a,b, Michael Caplan c, Hung-Chih Lin a,d,*

a
Department of Pediatrics, China Medical University Hospital, China Medical University, Taichung, Taiwan
b
School of Medicine, China Medical University, Taichung, Taiwan
c
The University of Chicago, Pritzker School of Medicine, Chicago, Illinois 60637, USA
d
School of Chinese Medicine, China Medical University, Taichung, Taiwan

Received Jun 28, 2011; received in revised form Sep 23, 2011; accepted Oct 12, 2011

Key Words The incidence of necrotizing enterocolitis (NEC) and mortality rate associated with this disease
early sign; are not decreasing despite more than three decades of intensive research investigation and
necrotizing advances in neonatal intensive care. Although the etiology of NEC is not clearly elucidated, the
enterocolitis; most accepted hypothesis at present is that enteral feeding in the presence of intestinal
probiotics hypoxia-ischemia-reperfusion, and colonization with pathogens provokes an inappropriately
accentuated inflammatory response by the immature intestinal epithelial cells of the preterm
neonate. However, delayed colonization of commensal flora with dysbiotic flora with a predomi-
nance of pathologic microorganisms plays a fundamental role in the pathogenesis of NEC. Recent
studies have further identified that NEC infants have less diverse flora compared to age-matched
controls without NEC. Increased gastric residual volume may be an early sign of NEC. An absolute
neutrophil count of <1.5  109 /L and platelets below 100  109 /L are associated with an
increased risk for mortality and gastrointestinal morbidity. Nonspecific supportive medical
management should be initiated promptly. Sudden changes in vital signs such as tachycardia or
impending shock may indicate perforation. A recent meta-analysis investigating using probiotics
for prevention of NEC with a total of 2176 preterm very low birth weight infants found a success
rate of just 1/25. Careful monitoring of the residual volume, and of serious changes in hemograms
and vital signs may help in early diagnosis and prediction of when to perform medical or early
surgical intervention. In term of prevention, administration of oral probiotics containing Bifido-
bacterium and Lactobacillus is a simple and safe method that attempts to early establish of
commensal flora balance to inhibit pathogenic flora and an inflammatory response.
Copyright ª 2012, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights
reserved.

* Corresponding author. Department of Pediatrics, China Medical University Hospital, China Medical University, No. 2 Yu-Der Road,
Taichung 404, Taiwan.
E-mail address: d0373@mail.cmuh.org.tw (H.-C. Lin).

1875-9572/$36 Copyright ª 2012, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.
doi:10.1016/j.pedneo.2012.04.001

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Necrotizing enterocolitis
1. Introduction
Necrotizing enterocolitis (NEC), an acute inflammatory
necrosis of the intestinal tract, is the most common
acquired gastrointestinal and surgical emergency for
preterm very low-birth weight (VLBW) infants in the
neonatal intensive care unit (NICU).1 Despite more than
three decades of intensive research investigation, little
progress has been made in the prevention and treatment of
NEC; in fact, despite advances in NICU care throughout the
world, the incidence and mortality associated with this
disease is not decreasing.2,3
2. Epidemiology
The incidence of NEC is inversely proportional to birth
weight (BW), with NEC affecting 11.5% of infants weighing
401 to 750 g, 9% of infants weighing 751 to 1000 g, 6% of
infants weighing 1001 to 1250 g, and 4% of infants weighing
1251 to 1500 g.4 Two sets of national data showed that the
incidence of NEC was relatively low in Taiwan (about 7%)5,6;
however, since fatality is a competing variable for NEC,
true incidence might be underestimated because the
mortality rate for VLBW infants was higher in Taiwan than in
the USA.
3. Etiology and pathogenesis
NEC is a complex disease and the etiology has not been
clearly elucidated. Multiple factors appear to contribute to
the pathogenesis:immaturity of multiple intestinal func-
tions includes gastrointestinal dysmotility, impaired diges-
tive capacity, altered regulation of intestinal blood flow,
barrier dysfunction, altered anti-inflammatory control, and
impaired host defense. It has been shown in experimental
systems that feeding, intestinal ischemia, and bacteria
could cause mucosal injury,7e9 and in preterm infants with
an altered pattern of bacterial colonization,10 provoke an
inappropriate accentuated proinflammatory response that
results in inflammatory necrosis of the bowel,11 and in some
cases, the systemic inflammatory response syndrome.12,13
It has been suggested that an unfavorable balance
between commensal and pathogenic bacteria is present in
the VLBW intestinal tract, and that this triggers a series of
cellular events that results in the pathogenesis of NEC.14,15
More recent studies using high-throughput molecular tech-
niques have identified differences in the diversity of
organisms present, and in one report it appeared that NEC
patients had lower diversity compared to age-matched
controls without NEC.16
Commensal bacteria can regulate the expression of
genes important for barrier function, digestion, and
angiogenesis.17 In vitro studies have demonstrated that
many species of commensal bacteria have the ability to
dampen the inflammatory response through inhibition
of the transcription factor nuclear factor kappa-B
(NF-kB).18,19 Endotoxin is known to bind to and activate
Toll-like receptor 4 (TLR4), and TLR4 mRNA expression has
been documented in fetal human intestine20 and is
increased in formula-fed and hypoxia-stressed rats.21 When
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159
lipopolysaccharide binds to TLR4, a series of chaperone and
signal transduction molecules are activated, which result in
NF-kB translocation from cytoplasm to the nucleus where
this important transcription factor activates the gene
expression of multiple proinflammatory cytokines.22
Following the activation of proinflammatory gene expres-
sion, multiple changes occur in neonatal intestine,
including accentuated apoptosis of epithelial cells,
perturbation of tight junctional proteins and complexes,
increased mucosal permeability, bacterial translocation,
alterations of vascular tone and microcirculation, and
additional neutrophil infiltration and accumulation.23e27
Thus,dysbiotic flora with a predominance of pathologic
microorganisms plays a fundamental role in the pathology
of NEC; animal studies have shown that severe NEC could
not be induced without the pathologic flora.28 It is likely
that the balance of pro- and anti-inflammatory signaling is
critical in maintaining intestinal homeostasis. Nonetheless,
it is hypothesized that the immature intestine responds to
injury with excessive inflammation and that this contrib-
utes to the final common pathway in the pathogenesis of
NEC.29,30 Many pro- and anti-inflammatory mediators are
involved in the pathogenesis of NEC based on animal or
human studies. Proinflammatory compounds that are up
regulated in NEC include platelet activating factor, tumor
necrosis factor, nitric oxide, interleukins (IL), such as IL-1b,
IL-6, IL-8, IL-12, and IL-18, and endothelin-1, leukotrienes,
thromboxanes, and oxygen-free radicals.31e39 Several anti-
inflammatory compounds down regulate intestinal inflam-
mation and these include prostacyclin, nitric oxide, several
growth factors such as epidermal growth factor, heparin-
binding epidermal growth factor, and insulin-like growth
factor, erythropoietin, IL-11, glutamine, and arginine.40e45
In addition, animal studies have shown that neonates have
an impaired ability to prevent NF-kB from entering the
nucleus in intestinal epithelial cells and activating the
production of multiple downstream proinflammatory
mediators.17e19 In summary, these results suggest that the
neonatal balance of the inflammatory response may be
weighted towards the proinflammatory side and more likely
to result in the pathologic outcome of NEC.
4. Diagnosis
Diagnosis of NEC is suspected when the characteristic
clinical features of abdominal distention, increased gastric
residual volume or frank emesis, and rectal bleeding are
present, and is confirmed by abdominal radiographic
evidence of pneumatosis intestinalis or portal venous air.
Increased residual gastric volume might be an early sign of
NEC. Radiological findings vary by gestational age; intra-
mural gas was detected in infants of 37 weeks’ gestational
age with NEC, but was only present in 29% of those of 26
weeks’ gestational age.46 Abdominal ultrasonography is
a newer technique to aid in the diagnosis of NEC47 and may
be more sensitive than abdominal radiography in detecting
bowel necrosis and alterations in bowel wall perfusion as
confirmed at laparotomy.48 The sonographic findings
include central echogenic focus of bowel wall and a hypo-
echoic rim (the pseudo-kidney sign) that indicate necrotic
bowel and imminent perforation. Ultrasonography also can
160
detect air bubbles in liver parenchyma and in the portal
venous system, and resolution of these findings is found to
correlate with safe re-initiation of enteral feedings.47
5. Laboratory evaluation
Sepsis evaluation should be performed when NEC is sus-
pected because 20% to 30% of infants will become bacter-
emic.49 An absolute neutrophil count <1.5  109/L is
associated with a poor prognosis.50 In addition, a platelet
count <100  109/L is associated with an increased risk for
mortality and gastrointestinal morbidity, and it is suggested
that declining platelet counts correlate with necrotic bowel
and worsening disease, whereas a subsequent rise in
platelet counts often signals improvement.51 Serial
increases in C-reactive protein and plasma lactate level
may predict progression of definite NEC to surgery or death
in preterm neonates.52 Additional laboratory abnormalities,
including persistent hyponatremia (serum sodium <130
meq/L), hyperglycemia, and metabolic acidosis are asso-
ciated with worsening disease.53
6. Differential diagnosis
Conditions such as sepsis, viral enteritis, and cow’s milk
protein allergy are difficult to distinguish from early signs of
NEC. A surgical disorder that closely mimics NEC is the
spontaneous intestinal perforation that typically presents
early in the neonatal course, and demonstrates free air on
a radiograph without evidence of pneumatosis intestinalis.
Other rare surgical conditions, including ileal atresia,
volvulus, internal hernia, neonatal appendicitis, and
intussusception, are often mistaken for NEC.
7. Medical management
Nonspecific supportive management should be initiated
promptly when NEC is suspected, but even with early
medical management, the progress of disease may still not
alter. Supportive care measures are aimed to limit the
progression of disease, and include discontinuation of
enteral feedings, gastrointestinal decompression with
intermittent nasogastric suction, fluid resuscitation, blood
pressure support, and correction of acidosis, electrolyte
disorders, anemia, and thrombocytopenia. Antibiotic
therapy and its duration in these patients should be
adjusted according to illness severity assigned by Bell’s
staging,54 the presence of peritonitis and/or perforation,
and the presence of sepsis.
8. Surgical intervention
Infants with NEC require surgical intervention when
necrosis extends through the bowel wall and results in
perforation. Additional surgical indications include perito-
nitis, the presence of an abdominal mass, ascites, intestinal
obstruction fixed dilated loop, or unremitting clinical
deterioration for an extended period of time.55 A sudden
change in vital signs, such as tachycardia, hypothermia, or
impending shock, might be a sign of perforation.Surgical
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S.-F. Wu et al
intervention with primary peritoneal drainage (PPD) or
laparotomy has been debated for several years in a multi-
center controlled study56 of 117 infants (<34 weeks
gestation) with perforated NEC to evaluate the benefit of
PPD versus laparotomy, no difference was noted between
PPD and laparotomy in mortality rate (34.5% vs. 35.5%), the
need for total parenteral nutrition (47.2% vs. 40%, respec-
tively) at 90 days postoperatively, or length of hospital stay.
The current standard of care allows treatment based upon
the judgment of the attending pediatric surgeon and
neonatology team. Infants that demonstrate clinical
improvement with stool passage spontaneously after PPD
may begin feedings without a contrast medium study and
never require a subsequent surgical procedure. In most
instances, laparotomy is indicated for patients who fail to
respond PPD.
9. Complications
Complications of NEC include sepsis, meningitis, perito-
nitis, abscess formation, disseminated intravascular coag-
ulation, hypotension, shock, and respiratory and renal
failure, and can occur during the acute stage of the disease
and immediate postrecovery stage. Late complications are
intestinal narrowing and short bowel syndrome, and rare
complications include enterocele, enterocolic fistula, and
intra-abdominal abscess.
Intestinal strictures are common, occur in 9% to 36% of
infants, and are unrelated to the severity of NEC, the
presence of pneumatosis intestinalis, or gestational age.57
The majority of strictures occur in the colon, although
the ileum and jejunum also are affected, and strictures at
multiple sites are common.58 Strictures typically develop
within 2 to 3 months of the acute episode but are some-
times detected as late as 20 months after the diagnosis.
Because of the high risk of stricture formation, the intes-
tinal contrast studies can be helpful in post-NEC patients if
feeding intolerance develops.
10. Prognosis
Mortality of infants with NEC was highest in infants of <27
weeks’ gestational age and in those with extensive
involvement of the small and large bowel.57,59 Data from
the Vermont Oxford Network60 demonstrated that the risk
of NEC and mortality decreased with increasing BW as
follows: BW 1251 to 1500 g, 3% risk of NEC, 16% died; BW
1001 to 1250 g, 6% risk of NEC, 21% died; BW 751 to 1000 g,
9% risk of NEC, 29% died; and BW 501 to 750 g, 12% risk of
NEC, 42% died. The majority of infants who had not had
extensive intestinal resection had normal gastrointestinal
function at age 1 to 10 years.
The Neonatal Research Network of National Institute of
Child Health and Human Development, showed that infants
of BW <1000 g who required surgical care were more likely
to have significant growth delay and poorer developmental
outcome at 18 to 22 months compared to those with-
outNEC61; the VLBW infants who were less sick with NEC
and only treated medically did not differ in growth or
developmental testing compared to those without NEC.62 In
a systematic review,63 NEC infants were twice as likely to
Necrotizing enterocolitis 161

be developmentally impaired compared to age-matched

controls, with increased risk for cerebral palsy, cognitive
impairment, and severe visual impairment.

11. Prevention

Given that the etiology of NEC is not clearly elucidated,

specific interventions to prevent or treat this disease are
lacking. Furthermore, NEC frequently progresses from early
signs of intestinal inflammation to extensive necrosis within
a matter of hours; thus, the development of preventive
strategies is indicated. Several approaches to prevent the
initiation of NEC have been attempted, but, for a variety
reasons, only breast milk feeding has attained consensus as
standard of care.64 Studies with preliminary success include
IgA supplementation, intravenous dexamethasone, enteral
antibiotics, polyunsaturated fatty acid supplementation,
lactoferrin, and arginine supplementation; however, due to
the inability to reproduce results and potential toxicities,
these approaches are not used routinely.
Probiotics are commensal bacteria that confer beneficial
effects to the host. They act on multiple mechanisms and
can promote maturation of intestinal barrier function,65
regulate apoptosis,66 reduce growth and adherence of
potentially pathogenic organisms,67 enhance the produc-
tion of anti-inflammatory cytokines68 and secretory IgA,69
attenuate the production nitric oxide,70 and increase
antioxidant activities.71 Different probiotics act on
different pathways, and since the etiology and pathogen-
esis of NEC is multifactorial, it is unlikely that a single agent
will effectively prevent the initiation of disease (Figure 1).
Clinical observations and animal studies suggest that
delayed colonization of commensal flora observed in
preterm infants could contribute to the development of
NEC.10 Caplan and Butel showed that Bifidobacteria
supplementation in neonatal rat and quail models result in
intestinal colonization and subsequent reduction in NEC-
Figure 2 Data on definite NEC were reported by all 11 trials
involing 2176 neonates.
like lesions.72,73 In reviewing the literature, there are
many clinical trials using probiotics in preterm VLBW
infants to prevent NEC or other outcomes. Of the studies,
only eleven randomized control trials could provide data to
examine the role of probiotics in the prevention of NEC.
From a total of 2176 neonates observed in these studies,
the number of infants need to be treated with probiotics to
prevent one case of NEC was 25; the relative risk was 0.35
(95% confidence interval: 0.23e0.55) in a recent meta-
analysis (Figure 2).74 Furthermore, a follow-up study at
corrected age 2 years showed that oral probiotics given to
premature VLBW infants after age 1 week to reduce the
incidence of NEC did not affect the growth and neuro-
developmental and sensory outcomes.75 Thus, use of pro-
biotics in VLBW infants is relatively safe on short-term and
long-term effects.
Based on these data, we believe that administration of oral
probiotics containing Bifidobacterium and Lactobacillus is

Figure 1 Effectiveness of Probiotics: rational of biologic pathomechanisms.

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162
a simple, safe, and noninvasive method that attempts early
establishment of commensal flora balance to inhibit patho-
genic flora and the inflammatory response.
Acknowledgment
The authors thank Drs W. B. Dobyns, W. Weiss and A. Sla-
votinek for their critical review of the manuscript.
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